Optionally 6-methylated and optionally 17-alkanoyloxygenated 2-oxapregnane-3, 20-diones, a-homo compounds corresponding, and 4, 5-dehydro and 4, 5; 6, 7-bisdehydro derivatives thereof



United States Patent Ofiice Patented Mar, 5, 1963 OPTIONALLY G-METHYLATED AND OPTIONAL- LY 17-ALKANOYLOXYGENATED Z-OXAPREG- NANE-3,20-DIONES, A-HOMO COMPOUNDS CQR- RESPONDING, AND 4,5-DEHYDRO AND 4,5;6,'7- BISDEHYDRO DERIVATIVES THEREOF Raphael Pappo, Skolrie, Ill., assignor to G. i). Searle &

(30., Chicago, IiL, a corporation of Delaware No Drawing. Filed Feb. 16, 1962, Ser. No. 173,800 17 Claims. (Cl. 260-3433) can be hydrogen or a methyl radical, and the dotted lines indicate the optional presence of double bonds between carbon atoms 4 and 5 and between carbon atoms 6 and 7. The lower alkanoyl radicals encompassed by the R term are, typically, formyl, acetyl, propionyl, butyryl, valeryl, caproyl, and the branched-chain isomers thereof.

Star-ting materials suitable for the manufacture of the instant l0-methyl-2-oxa compounds are the pregna-l,4- diene-3,20-diones of the structural formula =0 CH3 iin wherein R is hydrogen or a (lower alkanoyDoxy group and R is hydrogen or a methyl radical. These 1,4-dienes are converted to the corresponding 1,2-diols, suitably by reaction with potassium chlorate in the presence of a catalytic quantity of osmium tetroxide. Cleavage of these 1,2- diols, preferably by treatment with lead tetracetate, produces the intermediate 1,2-seco-A-norpregn-3-en-2-oic acids, which exist as an equilibrium mixture of the aldehydo-acid and lactol forms as is represented below:

in which representation R and R have the identical meanings indicated supra. The 2-oxa-A compounds of this invention which possess an oxygenated function at carbon atom 17 are obtained directly by reduction of the latter 1,2-seco-2-oic acids, suitably by means of a reducing agent such as sodium borohydride. In the case of the instant 2-oxa-A compounds which lack a l7-oxygen-containing function, this reduction step results also in conversion of the 20-ox-o group to a ZO-hydroxy function. Oxidation of the resulting 20-hydroxy substances, suitably bymeans of chromic acid, affords the desired instant 2'-oxapregn-4-ene- 3,20-diones. These processes are specifically illustrated by the reaction of pregna-1,4-diene-3,20-dione with potassium chlorate and osmium tetroxide in aqueous tertiarybutyl alcohol to yield 1,2-dihydroxypregn-4-ene-3,20- di-one, cleavage of the latter 1,2-dial by means of lead tetracetate in aqueous acetic acid to produce 1,20-dioxol,2-seco-A-norpregn-3-en-2-oic acid, reduction of the lat: ter aldehyde-acid in chloroform with alkaline sodium borohydride to afford 20-hydroxy-2-oxapregn-4-en-3-one, and oxidation of that ZO-hydroxy substance in acetone with aqueous chromic acid to yield 2-oXapregn-4-ene-3,20- dione.

Catalytic hydrogenation of the instant 2-oxa-A compounds, preferably in the presence of a palladium catalyst, affords the 2-oxa-4,5-dihydro compounds of this invention. For example, the aforementioned 2-oxapregu-4-ene- 3,20-dione in ethanol is treated with hydrogen in the presence of 10% palladium-onacarbon catalyst to aiford a mixture of the 50 and 5,9 isomers of 2-oxapregnane-3,20- dione, which are separable chromatographically. These 4,5-dihydro compounds are obtained also in the aforementioned sodium borohydride reduction process of the intermediate :aldehydo-acids. For example, the reduction of 1,20-dioxo 1,2 seco A norpregn-B-en-Z-oic acid, described supra, attords also 20-hydroXy-2-0Xapregnan-3- one. Chromic acid oxidation of that substance affords the 50c and 5B epimers of 2-oxapregnane-3,20-dione.

A method particularlysuitable for the preparation of the 4,5;6,7-bisdehydro compounds of this invention utilizes as the starting material, mula a compound of the forwherein R is a lower alkanoyl radical of the type defined above, and R can be hydrogen or a methyl radical. As a specific example, 17a-acetoxy 3 hydroxy-6-methy1- pregn-S-en-ZO-one is epoxidized, typically with perbenzoic acid, to produce 17ot-flCCtOXy-50t,6a-6pOXy-3fi-hydroxy-6,8methylpregnan-ZO-one together with the corresponding 5B,6B-epoxide. Reaction of either of the 'latter 'epoxides in acetone with aqueous chromic acid affords 17et-acetoxy 50;,6 9 dihydroxy-6a-methylpregnane- 3,2=0-dione, which yields 17a-acetoxy-6fl-hydroxy-6amethylpregna-l,4-diene-3,2Odione upon treatment with dichlorodicyanoquinone in benzene. The corresponding isomeric 6m-hydroxy-6fl-methyl compound is obtained by reacting the aforementioned 17oz-acetoxy-5a,6a-epoxy- 3 S-hydroxy-63-methylpregnan-20-one with chromium trioxide in pyridine to afford 17a-acetoxy-6ot-hydroxy-6B- methylpregn-4-ene-3,20-dione, and allowing the latter compound to .react with dichlorodicyanoquinone in benzene, thus producing .l,7u'-acetoxy-6a-hydroxy-6fi-methyl pregna-1,4-diene-3,20-dione. Either of the .two 69h) droxy-G-methyl isomers can be utilized in the following sequence of reactions to obtain the desired compounds of this invention. Typically, l7a-acetoxy-6fi hydroxy-6amethylpregna-l,4-diene-3,20-dione is converted to the corresponding 1,2-g1ycol upon reaction with osmium tetroxide and potassium-chlorate in aqueous tertiary-butyl alcohol. Cleavage of that glycol with lead tetracetate and acetic acid aifords 17a-acetoxy-6fi-hydroxy-6a-methyl-1- oxo-1,2-seco-A-norpregn-3-en-2-oic acid, which is converted to 17a-acetoxy-6B-hydroxy-6a-methyl-2-oxapregn- 4-ene-3,20-dione by reduction, suitably with sodium borohydride in isopropyl .alcohol. Dehydration of that 6- hydroxy compound, suitably by heating in toluene solution with p-toluenesulfonic acid or, alternatively, by reaction with phosphorus oxychloride in pyridine, results in the instant l7a-acetoxy-6-methyl-Loxapregna'4,6-diene-3,20-dione.

A process particularly advantageous for the manufaclure of the 3-oxa compounds of this invention utilizes as the starting material a compound of the formula :0 CH? i I ll wherein R is hydrogen or a (lower alkanoyDoxy radical, and R is hydrogen or a methyl radical. Thelatter sub- CHa =0 OH: I

followed by reaction with an alkali metal acetate and hydrolysis of the resulting 2a-ace'toxy compound. As a specific example, l7a-acetoxypregn-4-ene-3,ZO-dione is treated with N-bromosuccini'mide' in-carbon tetrachloride, and the resulting 6-bromo derivative is allowed to react with potassium acetate in acetic acid to yield 20,17oc-diacetoxypregn-4-ene-3,ZO-dione. Hydrolysis of that acetate, for example with potassium hydroxide in aqueous methanol, affords l7ot-acetoxy 2a hydroxypregn-4-ene- 3,20-dione. The 2a-hydroxy intermediates containing a 6a-methyl substituent are preferably obtained by reacting the 6a-methyl substances represented by the latter structural formula with lead 'tetracetate in acetic acid. Hydrolysis of the resulting Za-acetoxy derivative affords the required 211 -hydroxy intermediates. Typically, 17aacetoxy-6a-methylpregn-4-ene-3,20-dione is allowed to react with lead tetracetate in acetic acid to yield 2u,17a-diacetoxy-6a-methylpregn-4-ene-3,2 0-dione, which affords l7ot-acetoxy 2a hydroxy-6a-methylpregn-4-ene-3,2'0-dione upon reaction with potassium hydroxide in aqueous methanol.

Reaction of the aforementioned Za-hYdI'OXY intermediates with periodic acid in aqueous pyridine results incleavage of the A-ring to yield the corresponding 2,20- dioxo-2,3-secropregn-4-en-3-oic acids, which are in equihbnum with the lactol form, as is represented below:

Reaction of the latter 2-oxo-2,3-seco intermediates with a suitable reducing agent produces the corresponding 2- hydroxy compounds, which are converted to the instant 3-oxa-4-ones by heating. Those intermediates lacking a l7a-(lower alkanoyDoxy snbstituent produce 2,20-dihydroxy derivatives upon reduction, thus necessitating an additional oxidation step to regenerate the ZO-keto group. The latter processes are specifically illustrated by the reaction of 2a-hydroxypregn-4-ene-3,20 dione with periodic acid dihydrate in aqueous pyridine to afford 2,20- dioxo-2,3-secopregn-4-en-3-oic acid, which is treated with aqueous sodium borohydride, resulting in 2,20-dihydroxy-2,3 -secopregn-4-en-3-oic acid. The latter hydroxy-acid is heated at about 100 to yield 20-hydroxy-3- oxa-A-hornopregn-4a-en-4-one, which is oxidized, for example with chromium trioxide in acetone, thus producing 3-oxapregn-4a-ene-4,20-dione.

The 19-nor compounds of this invention are conveniently manufactured by utilizing as a starting material, 6-.oxo-5a-pregnane-S'B,20fl-di0l -3,20-diaceta'te, described 7 by I. Iwai and J. Hiraoka, Chem. and Pharm. Bull.

Japan, 7:395 (1959). Reaction of this material with hydrogen and platinum oxide in acetic acid or reaction with methyl magnesium bromide, followed by acidification and reacetylation, aifords the 6,8-hydroXy and 6,8- hydroxy-Ga-methyl compounds, respectively, of the structural formula I w t CHO C--CHa CH wherein R is hydrogen or a methyl radical. Reaction of the latter substances with lead tetracetate affords the corresponding 66,19-epoxy compounds, which are hydrolyzed, typically with alkali, to afford the 6,6,l9-epoxy- 3,20-diols. Oxidation of these diols, for example with chromic acid, produces the corresponding 65,19-epoxy- 3,20-diones. The latter diones are converted to the corresponding l7a-acyloxy intermediates, suitably by the following sequence of reactions. The 3-keto group is protected by treatment with methanol and acid to yield the dimethyl ketal, which is treated with oxygen in the pres ence of potassium tertiary-butoxide, then with zinc and acetic acid to introduce the l7u-hydroxy moiety. Acylation of these 17x-01S, typically by means of a lower alkanoic acid anhydride in the presence of the lower alkanoic acid affords the corresponding 17a-alkanoates.

By the aforementioned processes are provided intermediates of the structural formula wherein R is hydrogen or a (lower alkaneyDoxy radical and R is hydrogen or a methyl radical. Treatment of these intermediates with bromine followed by dehydrobromination, typically by heating with collidine, yields the corresponding l-dehydro compounds, which are oxidized with chromic acid, then treated with alkali and finally acetylated to afford the corresponding 6,8-acetoxyl9-n0r substances. Cleavage of the 1,2-double bond, suitably by reaction with lead tetracetate and osmium tetroxide, followed by treatment with a reducing agent such as sodium borohydride, then regeneration of the 20-oxo group in the case of the compounds lacking the 17macyloxy substituent, affords the 6fl-acetoxy-2-oxa-3,20 diones. Reaction of these substances with alkali affords the corresponding 6B-hydroxy compounds, which are dehydrated and isomerized, typically by means of phos- "t3 phorus oxychloride and pyridine to afford the desired 2-oxa compounds of the structural formula wherein R is hydrogen or a (lower alkanoyDoxy radical and R is hydrogen or a methyl radical.

The latter processes are specifically illustrated by the following sequence of reactions. The aforementioned 6-oxo-5a-pregnane-3[3,20fi-diol 3,20-diacetate is treated with hydrogen and platinum oxide in acetic acid to afford 5a-pregnane-35,6,43,20,8-triol 3,20-diacetate, which is converted to 6e,19-epoXy-5a-pregnane6d20fi-diol 3,20-diacetate by reaction with lead tetracetate. Hydrolysis of the latter di-ester by means of sodium hydroxide, followed by chromic acid oxidation produces 6,8,19-epoxy- Sa-pregnane-3,ZG-dione. Bromination followed by dehydrobromination, typically by heating with collidine, yields 6/3,l9-epoxy-5a-pregn-l-ene-3,ZO-dione, which is treated with chromium trioxide to afford the corresponding 19-oxo compound. Treatment of that substance with alkali followed by acetylation with acetic anhydride results in 6,8-acetoxy-l9-nor-5a-pregn-1-ene-3,20-dione. Re action of this compound with lead tetracetate and osmium tetroxide affords 6/3-acetoxyl-hydroxy-2-oxa-19-nor-5apregnane-3,20-dione. Reduction of the latter lactol, suitably with sodium borohydride, followed by acidification and treatment with chromium trioxide produces 6,8-acetoxy-Z-oxa-l9-nor-5ot-pregnane-3,20-dione. Reaction with alkali to afford the 6,8-01, then dehydration, typically with phosphorus oxychloride and pyridine, affords 2-oxal9-norpregn-4-ene-3,ZO-dione.

When the aforementioned 6-oXa-5ot-pregnane-3B,20 B- diol 3,20-diacetate is treated with methyl magnesium bromide in tetrahydrofuran, the resulting product, after acidification and reacetylation, is 6u-rnethyl-Sa-pregnane- 3p,6fi,20[ -triol 3,20-diacetate. Utilization of this starting material in the processes described supra results in 60:- methyl-2-oxa-l9-norpregn-4-ene-3,ZO-dione.

The aforementioned 6,8,l9-epoxy-5a-pregnane3,20- dione can be converted to the corresponding 17a-acetoxy compound by ketalization of the 3-oxo group with methanol in the presence of a mineral acid, then introduction of the 17-hydroxy group by reaction with oxygen in the presence of potassium tertiary-butoxide followed by treatment with zinc and acetic acid, and finally acetylation with acetic anhydride and acetic acid in the presence of an acid catalyst. The resulting l7a-acetoxy-6fi,l9-epoxy- Sa-pregnane-SJO-diOne can be converted to l7a-acetoxy- Z-oxa-19-norpregn-4-ene-3,ZO-dione by the aforementioned processes.

The compounds of this invention display valuable pharmacological properties. They are hormonal agents as is evidenced, for example, by their potent progestational activity.

The invention will appear more fully from the examples which follow. These examples are set forth by way of illustration only and it will be understood that the invention is not to be construed as limited in spirit or in scope by the details contained therein, as many modifications in materials and methods will be apparent from this disclosure to those skilled in the art. In these examples, temperatures are given in degrees centigrade C.). Quantities of materials are expressed in parts by weight unless otherwise noted.

7 This application is a continuation-in-part of my copending application Serial No. 150,662, filed November 7, 1961.

Example 1 A solution of 65 parts of pregna l,4-diene-3,20-dione in 1170 parts of tertiary-butyl alcohol is diluted with 1300 parts of water, and the resulting suspension is treated successively with 12.42 parts of potassium chlorate and 6.21 parts of osmium tetroxide. This suspension is stirred at room temperature for about 2 weeks, then is concentrated at room temperature and reduced pressure to about 500 parts by volume. The black oily layer which forms is separated and dissolved in 294 parts of pyridine, treated with parts of sodium bisulfite in 150 parts of water, then stirred at room. temperature for about hours. This mixture is extracted with benzene, and the organic layer is separated, Washed successively with dilute hydrochloric acid, water, aqueous sodium hydroxide, and water, dried over anhydrous sodium sulfate, and evaporated to dryness at reduced pressure. Recrystallization of the residue from benzene aifords pure 1,2-dihydroxypregn-4rene-3,ZO-dione, which melts atabout 162- 173 It, exhibit maximain the infrared at about 2.80, 2:88, 3.41, 5.90, and 6.18 microns and also an ultraviolet absorption maximum at about 239 millimicrons with a molecular extinction coefiicient of about 12,100.

Example 2 To a solution of 355- parts of 1,2-dihydroxypregn-4- ene-3,2 0-dione in 84 partsv of acetic acid containing 12 parts of water is added 13.64 parts of lead tetracetate, and this reaction mixture is stirred at 50-60 for about 1% hours. The. unreacted tetracetate is destroyed by h a dition of 0.6 part of formic acid, and the resulting solution is diluted with water, then extracted with chloroform. The chloroform layer is washed successively with, dilute aqueous potassium carbonate and water, dried over anhydrous sodium sulfate, and evaporated to dryness at reduced pressure. Trituration of the crystalline residue with boiling benzene yields 1,20-dioxo-1,2-seco-A- norpregn-3-en-2-oic acid, M.P. about 213-220. It is further characterized by an ultraviolet absorption maximum of about 226.5 millimicrons with a molecular extinction coeflicient of about 14,300.

Example 3.

To. a solution of one part of 1,20-dioxo-1,2-seco-A- norpregn-3-en-2-oic acid in 19.4v parts of chloroform is added a solution of one part of sodium borohydride in 13 parts of water containing 1.3 parts by volume of 10% aqueous sodium hydroxide, and the resulting mixture is stirred at room temperature for about four hours. The layers are, then separated, and the organic solution is washed successively with dilute aqueous; sodium hydroxide, and water, dried over anhydrous sodium sulfate, and evaporated to dryness. The. residue is. crystallized from ether to afliord a mixture of the m and 20p isomers of 20-hydroxy-2-oxapregna4-en-3-one, melting at about 170-- 176".

The aqueous alkaline layer from the chloroform extraction is acidified, then extracted with chloroform to yield an organic solution, which is washed successively with dilute sodium hydroxide and water, dried over anhydrous sodium sulfate, and evaporated to dryness. Recrystallization of the residue from ether affords a mixture of the epimeric 20-hydroxy-2-oxapregnan-3-ones, melting at about 192-200.

Example 4 To a solution of 6 parts of 20-hydroxy-2-oxapregn-4- en-3-one in 16'parts of acetone is added dropwise, 6 parts by volume of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid. The addition of a small quanttiy of isopropyl alcohol results in destruction of the excess reagent, and the resulting solution is concentrated under nitrogen at room temperature to afford a residue which is extracted with benzene. The benzene layer is washed successively with Water, aqueous sodium hydroxide, and water, then dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure. Recrystallization of this residue from isopropyl alcohol affords pure 2-oxapregn-4-ene-3,20-dione, M.P. about 168-169". It is further characterized by an ultraviolet absorption maximum at about 223.5 millimicrons with a molecular extinction coeflicient of about 14,150, and is represented by the structural formula Example 5 A solution of 50 parts of 17a-acetoxypregna-1,4-diene- 3,20-dione in 1,092 parts of tertiary-butyl' alcohol is diluted with 700 parts of water, and the resulting mixture is treated with 7 parts of potassium chlorate and 3.5 parts of osmium tetroxide. This reaction mixture is stirred at room temperature for about 28 days, then is concentrated at reduced pressure to a volume of about 200 parts. Extraction of this residual mixture with chloroform affords an organic solution, which is concentrated to dryness. Fractional crystallization of the residue from benzene affords 17a-acetoxy-4,S-dihydroxypregn-l-ene- 3,20 dione and l7a-acetoxy-1,2-dihydroxypregn-4-ene- 3,20-dione.

The substitution of an equivalent quantity of 17a-propionoxypregna-l,4-diene-3,20-dione in the process of this example results in 4, 5-dihydroxy-17a-propionoxypregn-1- ene-3,20-dione and 1,2-dihydroxy-17a-propionoxypregn- 4-ene-3,20-dione.

Example 6 To 9 parts of the mixture of 17 u-acetoxy-4,5-dihydroxypregn 1 ene 3,20 dione and 17a. acetoxy 1,2 dihydroxypregn-4-ene-3,20-dione dissolved in parts of acetic acid containing 10 parts of water is added 30.3 parts of lead tetracetate, and the resulting reaction mixture is stirred at 5060 for about 1% hours. This mixture is diluted with chloroform, then washed successively with water, dilute aqueous potassium carbonate, and water dried over anhydrous sodium sulfate, and evaporated to dryness. Trituration of the residue with benzene followed by recrystallization from chloroform results in pure 17aacetoxy 1,20 dioXo 1,2 seco A norpregn 3 en- 2-oic acid, which melts at about 285-288. It displays a maxima in the ultraviolet at about 226 millimicrons with a molecular extinction coeflicient of about 14,400.

By substituting an equivalent quantity of the mixture of 4,5 dihydroxy 17a propionoxypregn 1 ene 3,20- dione and l,Z-dihydroxy-l7a-propionoxypregn-4-ene-3,20- dione in the procedure of this example, l,20-dioxo-l7apropionoxy-1,2-seco-A-norpregn-3-en-2-oic acid is obtained.

Example 7 A mixture of 2.73 parts of 17u-acetoxy-l,20-dioxo-l,2- seco-A-norpregn3-en-2-oic acid, 2.7 parts of sodium borohydride and 35.6 parts of isopropyl alcohol is stirred at room temperature for about 10 minutes, at the end of which time the mixture becomes homogeneous. This solution is allowed to stand at room temperature for about 1% hours, then is cooled by means of an ice bath and treated with 40 parts of acetone. This mixture is poured into an ice-cold solution containing 40 parts of acetone,

9 200 parts of Water, and 12 parts of concentrated hydrochloric acid. Removal of the solvents by evaporation at reduced pressure affords a residue, which is extracted with chloroform. The resulting organic solution is separated, Washed successively with cold dilute aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, then evaporated to dryness at reduced pressure. Recrystallization of the residue from isopropyl alcohol results in 17a-acetoxy-2-oxapregn-4-ene-3,20-dione, which melts at about 269-275". It displays an ultraviolet absorption maximum at about 223.5 millimicrons with a molecular extinction coeflicient of about 14,900. It is represented by the structural formula CH3 O j O C-CH:

process of this example affords 17oc-propionoxy-2-oxapregn-4-ene-3,20-dione.

Example 8 To a solution of 10 parts of l7a-acetoxy-6a-methylpregna-l,4-diene-3,20-dione in 70.6 parts of pyridineis added, at 5, a solution of 6.64 parts of osmium tetroxide in 39.2 parts of pyridine. This reaction mixture is stored at room temperature for about 5 days, then is stirred with a solution of 30 parts of sodium bisulfite in 500 parts of water containing 294 parts of pyridine for about 15 hours. This aqueous mixture is extracted with chloroform, and the organic layer is Washed successively with Water, cold dilute hydrochloric acid, and water, dried over anhydrous sodium sulfate, and evaporated to dryness at reduced pressure to afford 17a-acetoxy-1,2-dihydroxy-6u-methylpregn-4-ene-3,2O-dione.

The substitution of an equivalent quantity of 6a-methyl- 17u-propionoxypregna-1,4-diene-3,20-dione in the process of this example results in 1,2-dihydroxy-6oa-methyl-17o:- propionoxypregn-4-ene-3,20-dione.

Example 9 A solution of 10 parts of 6a-methylpregna-1,4-diene- 3,20-dione in 75 parts of pyridine is cooled to about 5, then is treated with a solution of 5.7 parts of osmium tetroxide in 40 parts of pyridine. After standing at room temperature for about 5 days, a solution of 30 parts of sodium bisulfite in 500 parts of water containing 300 parts of pyridine is added, and the resulting mixture is stirred for about 16 hours. Extraction of this aqueous mixture with chloroform yields an organic solution, which is Washed successively with Water, dilute hydrochloric acid, and water, then dried over anhydrous sodium sulfate, and concentrated to dryness in vacuo to afford 1,2 dihydroxy-6oc-methylpregn-4-ene-3,20-dione.

Example 10 A solution of 3 parts of 17a-acetoxy-1,2-dihydroxy-6amethylpregn-4-ene-3,ZO-dione in 35 parts of acetic acid containing 3.3 parts of water is treated with 10.1 parts of lead tetracetate. This reaction mixture is heated at 50 60, with stirring, for about 2 hours, then is cooled and diluted with chloroform. The resulting mixture is washed successively with water, aqueous potassium carbonate, and Water. The washed chloroform solution is dried over anhydrous sodium sulfate, then is evaporated to dryness to produce 17a-acetoxy-6a-methyl-1,20-dioxo-1,2-seco- A-norpregn-3-en-2-oic acid.

10 By substituting an equivalent quantity of 1,2-dihydroxy 6a methyl 17a propionoxypregn 4 ene- 3,20-dione and otherwise proceeding according to the processes of this example, 6a-methyl-1,20-dioxo-17a-propionoxy-1,2-seco-A-norpregn-3-en-2-oic acid is obtained.

Example 11 A solution of 7.39 parts of 1,2-dihydroxy-6a-methy1- pregn-4-ene-3,20-dione in parts of acetic acid containing 25 parts of water is treated with 27.28 parts of lead tetracetate, and the resulting reaction mixture is heated with stirring at 50-60" for about 2 hours. The addition of 1.2 parts of formic acid destroys the unreac ted reagent. Water is then added, and the aqueous mixture is extracted with chloroform. The organic layer is purified by successive washings with dilute aqueous potassium carbonate and water, then is dried over anhydrous sodium sulfate. Concentration to dryness in vacuo produces 6a-methyl-1,20-dioxo-1,Zeeco-Amorpregn-S-en- 2-oic acid.

Example 12 The substitution of an equivalent quantity of 6a-methyl- 1,ZO-dioxo-1,2-seco-Anorpregn-3-en-2-oic acid in the procedure of Example 3 results in 20d1ydroxy-6a-methyl- 2-oxapregn-4-en-3-one.

Example 13 By substituting an equivalent quantity of 20-hydroxy- 6a-methyl-2-oxapregn-4-en-3-one and otherwise proceeding according to the processes of Example 4, 6a-methyl 2-oxapregn-4-ene-3,20-dione is obtained. It is represented by the structural formula G=O CH Example 14 0 CH3 l k OC--CHs and 6a-methyl 17a propionoxyQ-oxapregn-4-ene-3,20- dione of "the structural formula CHa Y j-- 0 oomorn To a solution of one part of 2oxapregn-4-ene-3.,20- dione in 80 parts of ethanol is added 0.2 part of 1.0%

palladium-on-carbon catalyst, and this mixture is shaken in a hydrogen atmosphere at atmospheric pressure .until one molecular equivalent of hydrogen is absorbed. 'Ihe catalyst is removed by filtration, and the filtrate is concentrated :to dryness under nitrogen to yield Z-oxapregnane- 3,20-.dione. Chromatography of this crude product on silica gel followed by elution with 50% ethyl acetate in benzene produces 2-oxa-5a-pregnane-3,20-dione, MP. about 189-191, of the structural formula and 2-oxa-5/3-pregnane3,ZO-dione of the structural formula GHa Example 16 The substitution'of an equivalent quantity of 6a-methyl- 2 oxapregn-4-ene-3,20-dione, l7aeacetoxy 2-oxapregn-4- -ene-3',20-dione, .17a-acetoxy 6a-methyl-2-oxapregn-4-ene- 3,20-dione, 6CD161lhYl-17OL-PIOPlOIlOXY-2-0Xap1'6g1'1-4-6l1e- 3,20-dione, or 170: -'propionoxy-2-oxapregn-4-ene 3,20- dione in the procedure of Example 15 results in the 50c and 5B isomers of 6ot-methyl-2-oxapregnane-3,20-dione, 17a-acetoxy-2-oxapregnane-3,20-dione, 17a acetoxy-6amethyl-2-oxapregnane-3,20-dione, 6oz methyl-lh-propionoxy-2 oxapregnane-3,20-dione, and 17oc-PIOPlOI1OXY-2- oxapregnane-3,20.-dione, respectively.

Example 17 1 2 Example 18 To asolution of 7.7 parts of 17a-acetoxy-3fi-hydroxy- 6-methylpregn-5-en-20-one in 67 parts of methylene chloride, cooled to 0-5,is added dropwise with stirring 40 parts by volume of a 0.5 molar perbenzoic acid solution in benzene, at such rate that the temperature does not rise above 25. After the addition is completed, this mixture is diluted with chloroform, then washed successively with aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and evaporated to dryness at reduced pressure. The resulting crystalline residue is recrystallized from methanol to afford pure l7a-acetoxy-5a,6a-

epoxy-3 3-hydroxy-6fl-rnethylpregnan-2O-one, melting at about 215-219".

The substitution of an equivalent quantity of id-hydroxy-6-methyl-17a-propionoxypregn-S-en-ZO- one in the processes of this example results in 5a,6a-epoxy-3 8-hydroxy-fl-methyl-17a-propionoxypregnan-20-one.

Example 19 To a solution of 1.16 parts of 17a-acetoxy-5a,6a-epoxy- 3;8-hydroxy-6fi-methylpregnan-20-one in 16 parts of acetone is added 0.9 part by volume of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid. This mixture -is stirred at room temperature fior about 3 minutes, then is treated with 0.1 part of isopropyl alcohol to destroy the excess reagent. Removal of the solvent at reduced pressure affords a residue, which is extracted with chloroform. This organic extract is washed successively with water, aqueous sodium hydroxide, and water, dried over anhydrous sodium sulfate, and concentrated to dryness under reduced pressure. Recrystallization of the residue from benzene affords pure 17a-acetoxy'5a,6;3- dihydroxy-6a methylpregnane 3,20 dione, MP. about 258-261 (dec.)

lBy substituting an equivalent quantity of 5a,6a-epoxy- 3fi-hydroxy-6p-methyhl7a propionoxypregnan 20 one and otherwise proceeding according to the hereindescribed processes, 5a,6B-dihydroxy-6a-methyl 17a propionoxypregnane-BJO-dione is obtained.

Example 20 To a solution of 4 parts of 17a-acetoxy-5u,6B-dihydroxy- 6a-methylpregnane-3,ZO-dione in 264 parts of benzene is added 2.7 parts of dichlorodicyanoquinone, and this reaction mixture is heated at reflux for about 16 hours, then is cooled and filtered. The filtrate is washed successively with aqueous sodium sulfite, aqueous sodium hydroxide and water, then is dried over anhydrous sodium sulfate and evaporated to dryness to afford 17u-acetoxy-6B-hydroxy-6wmethylpregna-IA diene 3,20 dione. Recrystallization from benzene afiords a pure sample melting at about 274-2822 It is further characterized by an ultraviolet maximum at about 244 millimicrons with a molecular extinction coefificient of about 15,200.

The substitution of an equivalent quantity of 50:,65- dihydroxy-6a-methyl-17a propionoxypregnane 3,20 dione in the procedure of this example affords 6B-hydroxy- 6 t-methyl-l7 z-propionoxypregna-1,4-diene-3,20 dione.

Example 21 To a solution of, 6 parts of 17a-acetOXy-Sa,6 8-dihydroxy- 6a-methylpregnane-3,ZO dione in 88 parts of benzene and 67" parts of methylene chloride is added 7 parts of Woelm basic alumina (activity I), described by H. Brockmann et al., Ben, 74, 73 (1941), and the mixture is stirred at room temperature for about 60 hours. The catalyst is removed by filtration and washed on the filter with 50% benzene in methylene chloride. The filtrate is evaporated to dryness to afford colorless prisms of 17a-acetoxy-6phydroxy-6wmethylpregn-4 ene 3,20 dione, M.P.' about 223-225". It displays an ultraviolet maximum at about 237.5 millimicrons with a molecular extinction coefiicient of about 13,200.

13 By substituting an equivalent quantity of fi-hydroxy- Ga-methyl-17a-propionoxypregnane-3,20-dione and otherwise proceeding according to the herein-described processes, 6,8hydroxy-6a-*nethyl-17a-propionoxypregn-4 ene- 3,2.0-dione is obtained.

Example 22 The substitution of 4.1 parts of 17ot-acetoxy-6fi-hydroxy- 6e-methylpregn-4-ene-3,20-dione in the procedure of Example 20, results in 17ct-acetoxy-6/3-hydroxy-6a-methylpregna-1,4-diene-3,20-dione, identical with the product of Example 14.

Example 23 To a mixture of 3 parts of chromium trioxide with 30 parts of pyridine is added a solution of 1.5 parts of 17aacetoxy-Safia-epoxy-S{3-hydroxy-6B methylpregnan 20- one, and the reaction mixture is stirred at room temperature for about 2 /2 hours, then is stored at room temperature for about 16 hours. The suspension is diluted with benzene and filtered. The filtrate is washed successively with water, 5% aqueous sodium hydroxide, and water, dried over anhydrous sodium sulfate, and stripped oi solvent at room temperature and reduced pressure. Recrystallization of the residue from benzene aifords 170L- acetoxy-6a-hydroxy-6,6-methylpregn-4 ene 3,20 dione, MP. about 246-249". It exhibits an ultraviolet maximum at about 242 millirnicrons with a molecular extinction coefficient of about 13,600.

The benzene mother liquor is concentrated to dryness to yield 17aacetoxy-5a,6cc-epoxy-GB-methylpregnane-I:,20- dione, MP. about 204-216".

The substitution of an equivalent quantity of 5zx,6oc epoxy-3,8-hydroxy6,B-rnethyl-1 7a-propionoxypregnan 20- one in the procedure of this example affords 6a-hydroxy- 6,6-rnethyl-17a-propionoxypregn-4 ene 3,20 dione and 5a,6a-epoxy-6[3-methyl 17oz propionoxypregnane 3,20- dione.

Example 24 A solution of one part of 17a-acetoxy-5a,6e-epoxy-6B- methylpregnane-3,20-dione in 20 parts of pyridine is allowed to stand at room temperature for about 16 hours, then is concentrated to dryness to afford 171x-acetoxy-6ahydroxy-6fi-methylprcgn-4-ene-3,20-dione, identical with the product of Example 23.

Example 25 The substitution of 3.9 parts of 17OC-aC6tOXy-60t-hydrox -6,B-methylpregn-4-ene-3,ZO-dione or 4 parts of 60ahydroxy-6/3-methyl-17a-propionoxypregn-4-ene-3,ZO-dione in the procedure of Example 20 results in 17a-acetoxy- 6.x-hydroxy-6/3-methylpregna-1,4-diene-3,20-dione and 60ahydroxy-dfi-methyl-17a-propionoxypregna-l,4-diene-3,20- dione, respectively.

"xample 26 To a solution of 38 parts of 17c -acetoxy6,8-hydroxy- 6a-rnethylprcgna-1,4-diene-3,20-dione in 390 parts of tertiary-butyl alcohol containing 400 parts of water is added 2.5 parts of osmium tetroxide and 4.9 parts of potassium chlorate, and this mixture is kept at room temperature for about 14 days, then is concentrated at reduced pressure and room temperature to a small volume. The oily layer which separates is dissolved in 150 parts of pyridine and treated with a solution of 6 parts of sodiurn bisulfite in 90 parts of water. This mixture is strirred for about 15 hours, then is extracted with benzene. The benzene layer is washed successively With dilute hydrochloric acid, water, aqueous sodium hydroxide, and water, dried over anhydrous sodium sulfate and concentrated to dryness at reduced pressure to yield 17o:-acetoXy-l,2,6/S- trihydroxy-6a-methylpregn-4-ene-3,20-dione.

By substituting an equivalent quantity of 6fl-hydroxy- 6a methyl-17a-propionoxypregna 1,4 diene-3,20-dione, and otherwise proceeding according to the processes of 1% this example, 1,2,6,8-trihydroxy-6wmethyl-17a-propionoxypregn-4 ene-3,20-dione is obtained.

Example 27 A mixture of 4.1 parts of 17a-acetoxy-1,2,6fi-trihydroxy-6x-metl1ylpregn-4-ene-3,20-dione, 14.5 parts of lead tetracetate, 35 parts of acetic acid, and 5 parts of water is heated at 5060 for about 1 /2 hourswith stirring, then is treated with 0.6 part of formic acid and is diluted with water. Extraction with chloroform affords an organic solution, which is Washed successively with dilute aqueous potassium carbonate and Water, dried over anhydrous sodium sulfate, and concentrated to dryness at reduced pressure, resulting in l7u-acetoxy-6fl-hydroxy- 6ot-rnethyl1,20-dioxo-1,2seco-A-norpregn-3-en-2-oie acid.

The substitution of an equivalent quantity of 1,2,6B-trihydroxy 6a methyl 170: propionoxypregn-4-ene-3,20 dione in the procedure of this example affords 6fl-hydroxy-6oi-methyhl,20-dioxo-17a-propi0noxy-L2-seco A norpregn-3-en-2-oic acid.

Example 28 A mixture of 5.4 parts of 17a-acetoxy-Gfi-hydroxy-Samethyl-1,20-dioxo-1,2-seco A norpregn-3-en-2-oic acid, 5.4 parts of sodium borohydride, and 70 parts of isopropyl alcohol is stirred at room temperature for about 2 hours, then is cooled by means of an ice bath and treated with parts of acetone. The resulting mixture is added to an ice-cold solution consisting of 80 parts of acetone, 400 parts of water, and 24 parts of concentrated hydrochloric acid. This mixture is concentrated to dryness at reduced pressure, and the resulting residue is extracted with chloroform. The organic layer is then washed successively with cold dilute aqueous sodium hydroxide and water, is dried over anhydrous sodium sulfate, and is concentrated to dryness at reduced pressure to afford 17aacetoxy-6/3-hydroxy-6a-methyl 2 oxapregn-4-ene-3,20- dione.

By substituting an equivalent quantity of 6p-hydroxy- 60c methyl 1,20 dioxo-17a-propionoxy-1,2-seco-A-norpregn-S-en-Z-oic acid and otherwise proceeding according .to the herein-described processes 6,6-hydroxy-6otmethyl-17ot-propionoxy-2-oxapregn-4-ene-3,20-dione is obtained.

Example 29 0A or) The substitution of an equivalent quantity of 65- hydroxy-6wrnethyl 17cc propionoxy-2-oxapregn-4-ene- 3,20-dione in the procedure of this example results in 6- methyl-17tic-propionoxy2-oxapregna-4,6-diene-3,20-dione.

Example 30 A mixture of 4 parts of 17oc-ElOEtOXY-GB-hYdIOXY-6ozmethyl-2-oxapregn-4-ene-3,20 dione, 1.3 parts of phosphorus oxychloride, and parts of dry pyridine is stored at room temperature for about 16 hours. Water and ice are added, and the resulting aqueous mixture is extracted with chloroform. The chloroform layer is separated, washed successively with dilute hydrochloric acid, water, dilute aqueous sodium hydroxide, and water, dried over anhydrous sodium sulfate and evaporated to dryness in vacuo to afford 17a-acetoxy-6-methyl-2-oxapregna-4,6- diene-3,20-dione, identical with the product of Example 29.

The substitution of an equivalent quantity of 6,8-hy droxy 6a-methy1-17a-propionoxy-2-oxapregn-4-ene-3,20- dione in the procedure of this example results in 6-methyl- 17ot-propionoxy-2-oxapregna-4,6-diene-3,ZO-dione, identical with the product of Example 29.

Example 31 A mixture of 39 parts of 17a-acetoxy-6a-methylpregn- 4-ene-3,20-dione, 53 parts of lead tetracetate and 630 parts of acetic acid is heated at 80-85 with stirring for about 2 hours, then is diluted with water and extracted with benzene. The benzene extract is washed successively with water, aqueous sodium hydroxide, and Water, dried over anhydrous sodium sulfate, and concentrated to dryness. The resulting residue is dissolved in benzene and chromatographed on silica gel. Elution with 20% ethyl acetate .in benzene affords 2a,17a-diacetoxy-6u-methylpregn-4-ene-3,20-dione.

By substituting an equivalent quantity of 6u-rnethyl- 17a-propionoxypregn-4-ene-3,ZO-dione and otherwise proceeding according to the processes of this example, 20:- acetoxy 6a methyl 17ct-propionoxypregn-4-cue-3,20- dione is obtained.

Example 32 A mixture of 10 parts of 2a,17a-diacetoxy-6u-methylpregn-'4-ene-3,20-dione, 1.3 parts of potassium hydroxide, 240 parts of methanol, and 20 parts of water is stirred at room'temperature for about minutes, then is acidified with acetic acid and concentrated to a small volume at reduced pressure. The residue is diluted with Water, then extracted with chloroform. The organic extract is washed successively with aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and stripped of solvent at reduced pressure to yield 17a-acetoxy-2m-hydroxy-6a-methylpregn-4-ene-3,20-dione.

The substitution of an equivalent quantity of 2a-acetoxy- 6a-methyl-17a-propionoxypregn-4-ene-3,20-dione in the procedure of this example results in 2a-hydroxy-6a-methyl-l7a-propionoxypregn-4-ene-3,20-dione.

Example 33 To a solution of 37 parts of 17a-acetoxypregn-4-ene- 3,20-dione in 800 parts of dry carbon tetrachloride is added 20 parts of N-bromosuccinimide, and the reaction mixture is heated at reflux with stirring for about one hour, while being subjected to infrared irradiation. This mixture is cooled, washed successively with water, aqueous sodium sulfite and water, dried over anhydrous sodium sulfate, and evaporated to dryness to yield 170t-flCCtOXy- 6-bromopregn-4-ene-3,20-dione.

A mixture of the crude 17a-acetoxy-6-bromopregn-4- ene-3,20-dione, 120 parts of potassium acetate, and 788 parts of acetic acid is heated at reflux for about one hour, then is cooled, diluted with water, and extracted with benzene. The benzene extract is washed successively with water, dilute aqueous sodium hydroxide, and water, then is dried over anhydrous sodium sulfate and stripped of solvent in vacuo, Chromatography of a benzene solution of the residue on silica gel followed by elution with 20% ethyl acetate in benzene affords 2a,17ot-diacetoxypregn- 4-ene-3,20-dione.

. 16 The substitution of an equivalent quantity of 17a-propionoxypregn-4-ene-3,20-dione in the processes of this example results in 2a-acetoxy-17a-propionoxypregn-4-ene- 3,20-dione.

Example 34 The substitution of 9.7 parts of 2a,17a-diacetoxypregn- 4-ene-3,20dione or 10 parts of 2a-acetoxy-l7a-propionoxypregn-4-ene-3,20-dione in the procedure of Example 32 results in 17wacetoxy-2a-hydroxypregn-4-ene-3,ZO-dione and 2a hydroxy-17a-propionoxypregni-ene,20-dione, respectively.

Example 35 A mixture of 4 parts of 17a-acetoxy-2a-hydroxy-6amethylpregn-4-ene-3,20-dione, 2.3 parts of periodic acid dihydrate, 40 parts of pyridine, and 10 parts of water is stirred at room temperature for about 36 hours. The reaction mixture is then extracted with chloroform, and the organic extract is washed successively with water and aqueous potassium carbonate. Extraction of this washed solution with ice-cold 5% aqueous sodium hydroxide affords an alkaline extract, which is acidified by means of excess acetic acid. The resulting precipitate is extracted with chloroform, and the chloroform extract is washed with water, then is evaporated to dryness under nitrogen to yield 17a-acetoxy-6a-methyl-2,20-dioxo-2,3-secopregn! 4-en-3-oic acid.

By substituting an equivalent quantity of 2u-hydroxyl7a-propionoxypregn-4-ene-3,20-dione or 2a-hydroxy-6w methyl-17a-propionoxypregn-4-ene-3,ZO-dione in the procedure of this example, 17ot-propionoxy-2,20-di0xo-2,3- secopregn-4-en-3-oic acid and 6ot-methyl-17a-propionoxy- 2,20-dioxo-2,3-secopregn-4-ene3-oic acid are obtained.

Example 36 A mixture of one part of 17oc-acetoxy-6a-methyle2,20- dioxo-2,3-secopregn-4-en-3-oic acid, 0.9 part of sodium borohydride and parts of anhydrous isopropyl alcohol is stirred at room temperature for about one hour, then is cooled by means of an ice-bath and treated with 8 parts of acetone. The resulting mixture is added to an ice-cold solution containing .40 parts of Water, 8 parts of acetone and 2.4 parts of concentrated hydrochloric acid, then is concentrated to a small volume at reduced pressure. The residue is diluted with water and extracted with chloroform. The organic layer is washed with water, dried over anhydrous sodium sulfate and stripped of solvent at reduced pressure and room temperature to produce 17a-acetoxy-2-hydroxy-6a-methyl-20-oxo 2,3-secopregn- 4-en-3-oic acid. On the other hand, concentration of the organic layer to dryness on the steam bath results in acetoxy 6a methyl-3-oxa-A-homopregn-4aene-4,20- dione, which is represented by the structural formula fijoooom (kg-y lHa 17 acid and 6u-methyl-l7a-propionoxy-3-oxa-A-homopregn- 4a-ene-4,20-dione.

Example 37 The substitution of 3.1 parts of 2u-hydroxypregn-4-ene- 3,20-dione or 3.2 parts of 2u-hydroxy-6a-methylpregn-4- ene-3,20-dione in the procedure of Example 35 results in 2,20-dioxo-2,3-secopregn-4-en-3-oic acid and Goa-methyl- 2,20-dioxo-2,3-secopregn-4-en-3-oic acid, respectively.

Example 38 A mixture of one part of 2,20 -doxo-2,3-secopregn-4- en-3-oic acid, one part of sodium borohydride, and 100 parts of water is stirred at room temperature for about one hour. The reaction mixture is cooled, acidified with excess hydrochloric acid and extracted with chloroform. The organic extract is washed with water, dried over anhydrous sodium sulfate, and concentrated at room temperature and reduced pressure to aiiord 2,20-dihydroxy- 2,3-secopregn-4-en-3-oic acid. Evaporation of the solvent on the steam bath, however, produces 20-hydroxy-3-oxa- A-homopregn-4a-en-4-one.

Example 39 A solution of one part of 20-hydroxy-3-oxa-A-homopregn-4a-en-4-one in 40 parts of acetone is treated with one part by volume of an aqueous solution, 8 N in chromium trioxide and 8 N in sulfuric acid, at room temperature for about 5 minutes. To the reaction mixture is then added 0.16 part of isopropyl alcohol. Concentration of this mixture to dryness under nitrogen at room temperature produces a residue, which is extracted with benzene. The organic layer is washed successively with water, aqueous sodium hydroxide and water, dried over anhydrous sodium sulfate, and evaporated to dryness at reduced pressure to yield 3-oxa-A-homopregn-4a-ene-4,20- dione of the structural formula Example 40 The substitution of one part of 6a-methyl-2,20-dioxo- 2,3-secopregn-4-en-3-oic acid in the procedure of Example 38 results in 2,20-dihydroxy-6a-methyl-2,3-secopregn-4- en-3-oic acid and 20-hydroxy-6a-methyl-3-oxa-A-homopregn-4a-en-4-one.

Example 41 The substitution of one part of 20-hydroxy-6oc-methyl- 3-oxa-A-homopregn-4a-en-4-one in the procedure of Example 39 results in 6a-methyl-3-oXa-A-homopregn-4a-ene- 4,20-dione of the structural formula 18 Example 42 The substitution of 3.9 parts of 17a-acetoxy-2a-hydroxypregn-4-ene-3,20-dione in the procedure of Example 35 results in 17oc-acetoxy-2,20-dioxo-2,3-secopregn-4-en-3-oic acid.

Example 43 By substituting one part of 17a-acetoxy-2,20-dioxo-2,3- secopregn-4-en-3-oic acid and otherwise proceeding according to the processes of Example 36, 17a-acetoxy-2- hydroxy-20-oxo-2,3-secopregn-4-en-3-oic acid and 17aacetoxy 3 oxa-A-hornopregn-4a-ene-4,20-di0ne are obtained.

What is claimed is:

l. A member selected from the class consisting of compounds of the formula 17a-acetoxy-6a-methyl-2-oxapregnane-3,ZO-dione. A compound of the formula :---oo0 (lower alky 7. l7a-acetoxy-2-oxapregrr-4-ene-3,20-dione. 8. A compound of the formula CHa =0 --OCO (lower alkyl) 1 9 9. l7a-acetoxy- 6a-methyl-2-oxapregn-4-ene-3,ZO-dione. 110. A compound of the formula CHa =0 j --OO0 (lower alkyl) 11. 17a-acetoxy-2-oxapregnane-3,20-dione. 12. A compound of the formula =0 i --o0o (lower alkyl) 13. 17a-acetoxy fi-methyl-2-oxapregna-4,6-diene-3,20-

dione.

2t) 14. Acompound of the formula 5 OHa 10 wherein R is selected from the group consisting of hydrogen and (lower alkanoyl)oxy and R is selected from the group consisting of hydrogen and methyl.

15. 3-oxa-A-homopregn-4a-ene-4,20-dione.

16. A compound of the formula 

1. A MEMBER SELECTED FROM THE CLASS CONSISTING OF COMPOUNDS OF THE FORMULA 